The long-term objective of this application is to identify the pathophysiologic mechanisms responsible for myocyte cell death and reactive cellular growth responses which underlie the aging process of the heart in its evolution towards congestive heart failure (CHF). The major hypothesis to be tested is that aging of the heart results from alterations in diastolic function which occur early in life an trigger a sequence of interrelated events characterized by side-to-side slippage of myocytes, stress dependent myocyte cellular death, and profound wall and chamber remodeling. These cellular rearrangements are expected to affect the taransverse diameter and the longitudinal axis of the heart leading to an enlarged, thin wall ventricle and a marked increase in load on the myocardium. The sustained elevation in myocyte stress is postulated to be the mechanical stimulus for cellular hypertrophy and hyperplasia which would tend to reduce the work load on the individual myocytes. The inability of the cells to continue to grow in size and number to the magnitude required by the increase in stress, is considered the cause of ventricular dysfunction and failure with aging. A second relevant hypothesis to be tested is that the early impairment in cardiac hemodynamics is characterized by attenuation of signal transduction via the beta adrenergic receptor - adenylate cyclase complex, depressing contractility and further increasing the work load on the heart. This effect is believed to be initially counteracted by the activation of the alpha-1 adrenoreceptor signal transduction pathway which has been implicated as a proximate mediator of myocyte hypertrophy. Attenuation of this effector pathway is postulated to be coupled with the loss of the hypertrophic growth response of myocytes and progressive augmentation in myocyte stress which then initiates myocyte mitotic division. Myocyte hyperplasia is assumed to be mediated by an upregulation of membrane bound growth factor receptors and signal transduction mechanisms linked to these receptors whereas a depressed activity of these effector pathways will be associated with a decline in myocyte hyperplasia and irreversible CHF and death. Based on the hypothesis that hypertension enhances mechanical cell death and consumes the growth reserve of the myocardium, hypertension superimposed on aging is anticipated to result in the precocious appearance of severe ventricular dysfunction and failure. In contrast, drugs which reduce the load on the heart are expected to limit the phenomenon of myocyte cell death and ventricular remodeling and consequently prevent or postpone the detrimental effects of aging and its major risk factors on the heart.